Abstract
Pulmonary calcification and ossification occurs with a number of systemic and pulmonary conditions. Specific symptoms are often lacking, but calcification may be a marker of disease severity and its chronicity. Pathophysiologic states predisposing to pulmonary calcification and ossification include hypercalcemia, a local alkaline environment, and previous lung injury. Factors such as enhanced alkaline phosphatase activity, active angiogenesis, and mitogenic effects of growth factors may also contribute. The clinical classification of pulmonary calcification includes both metastatic calcification, in which calcium deposits in previously normal lung or dystrophic calcification, which occurs in previously injured lung. Pulmonary ossification can be idiopathic or can result from a variety of underlying pulmonary, cardiac, or extracardiopulmonary disorders. The diagnosis of pulmonary calcification and ossification requires various imaging techniques, including chest radiography, computed tomographic scanning, and bone scintigraphy. Interpretation of the presence of and the specific pattern of calcification or ossification may obviate the need for invasive biopsy. In this review, specific conditions causing pulmonary calcification or ossification that may impact diagnostic and treatment decisions are highlighted. These include metastatic calcification caused by chronic renal failure and orthotopic liver transplantation, dystrophic calcification caused by granulomatous disorders, DNA viruses, parasitic infections, pulmonary amyloidosis, vascular calcification, the idiopathic disorder pulmonary alveolar microlithiasis, and various forms of pulmonary ossification.
Clinical Classification of Pulmonary Calcification and Ossifi- cation
Proposed Mechanisms of Ectopic Lung Calcification and Os- sification
Role of Relative and Absolute Calcium Excess
Role of an Alkaline Environment
Role of Lung Injury or Fibrosis
Role of Angiogenesis
Imaging
Chest Roentgenogram
Computed Tomography
99mTc-MDP Bone Scintigraphy
Specific Disorders
Pulmonary Metastatic Calcification
Pulmonary Calcification Associated with Granulomatous Disorders
Pulmonary Calcification as a Sequela of Varicella or Other Viral Pneumonias
Pulmonary Calcification Associated with Parasitic Infections
Pulmonary Calcification Associated with Amyloidosis
Pulmonary Vascular Calcification
Pulmonary Alveolar Microlithiasis
Pulmonary Ossification
Conclusion
Although direct observation and palpation of thoracic calcification were noted by Laennec in his textbook of physical examination of the lungs (1), the interest in pulmonary calcification began with the advent of chest radiography in the late 19th century (2).
Calcification within the thorax results from disparate clinical states. The anatomic location and specific features of the calcification often provide insights into occult diseases and can sometimes explain respiratory symptoms. Ectopic calcification occurs in the chest wall, pleura, lung parenchyma, hilar and mediastinal lymph nodes, and pulmonary arteries (3). This review organizes the classification of the pulmonary parenchymal calcific and ossific disorders, outlines their probable or possible pathogenesis, summarizes methods of detection, and illustrates their clinico–radiographic–pathologic features. A discussion of calcified solitary pulmonary nodules is not included. The potential impact of calcification on diagnosis and treatment is highlighted whenever specific information is available.
Calcification refers to the deposition of calcium salts in tissues, in contrast to ossification, which indicates bone tissue formation (calcification in a collagen matrix), with or without marrow elements. A number of pathologic conditions predispose to soft tissue calcification. Internal organs most commonly affected by ectopic calcification include the stomach, kidneys, lungs, heart, and blood vessels. The lungs seem particularly susceptible to this complication. Pathologic soft tissue calcification can be broadly divided into either (1) metastatic calcification, in which calcium deposits in normal tissues, or (2) dystrophic calcification, in which calcification is superimposed on previously injured lung (Table 1)
I. Metastatic |
|---|
| A. Benign causes |
| 1. Chronic renal insufficiency on hemodialysis |
| 2. Orthotopic liver transplantation |
| 3. Primary hyperparathyroidism |
| 4. Excess exogenous administration of calcium and vitamin D (milk-alkali syndrome) |
| 5. Hypervitaminosis D |
| 6. Osteopetrosis |
| 7. Osteitis deformans (Paget's disease) |
| B. Malignant causes |
| 1. Parathyroid carcinoma |
| 2. Multiple myeloma |
| 3. Lymphoma/leukemia |
| 4. Hypopharyngeal squamous cell carcinoma |
| 5. Synovial sarcoma |
| 6. Breast carcinoma |
| 7. Choriocarcinoma |
| II. Dystrophic calcification |
| A. Granulomatous disorders |
| 1. Histoplasmosis |
| 2. Coccidioidomycosis |
| 3. Tuberculosis |
| 4. Sarcoidosis |
| B. Viral infections |
| 1. Postvaricella pneumonia |
| 2. Smallpox handler's lung |
| C. Parasitic infections |
| 1. Paragonomiasis |
| 2. Pneumocystosis |
| D. Amyloidosis |
| E. Pulmonary vascular calcifications |
| 1. Vascular grafts |
| 2. Pulmonary hypertension |
| 3. Congenital high flow |
| 4. Hemosiderosis |
| F. Coal worker's pneumoconiosis |
| G. Silicosis |
| III. Idiopathic |
| A. Pulmonary alveolar microlithiasis |
Metastatic pulmonary calcification is further subdivided into benign (4–15) and malignant causes (16–21) (Table 1). By far the most common cause of metastatic calcification is seen in patients on hemodialysis for chronic renal insufficiency. The other causes are uncommon (Table 1). Dystrophic calcification follows caseation, necrosis, or fibrosis and may complicate pulmonary infections that include (1) granulomatous infections, for example, Histoplasma capsulatum (22), Coccidioides immitis (23), and Mycobacterium tuberculosis (24); (2) viral infections, for example, varicella virus (25) and smallpox virus (26); and (3) parasitic infections, for example, Paragonimus westermani (27) and Pneumocystis carinii (28) (Table 1). In sarcoidosis, pulmonary calcification can result from either dystrophic calcification or metastatic calcification secondary to hypercalcemia (29, 30). Pulmonary vascular calcification (PVC) is postulated to result from shear stress and is considered to be a variant of dystrophic calcification (31). Dystrophic calcification has also been described in association with amyloidosis and after inhalation exposures in coal workers pneumoconiosis and silicosis. Pulmonary alveolar microlithiasis (PAM) is a unique idiopathic calcific disorder with distinct histologic and radiographic appearances that do not fit into either metastatic or dystrophic calcification (Table 1).
Clinical states that result in both calcium deposition and bone formation are listed in Table 2
I. Idiopathic pulmonary ossification |
|---|
| II. Preexisting pulmonary disorder |
| A. Idiopathic pulmonary fibrosis |
| B. Pulmonary amyloidosis |
| C. Chronic busulfan therapy |
| D. Acute respiratory distress syndrome |
| E. Hamman-Rich syndrome |
| F. Sarcoidosis |
| G. Histoplasmosis |
| H. Tuberculosis |
| I. Metastatic breast cancer |
| J. Pulmonary metastases of osteogenic sarcoma |
| K. Metastatic melanoma |
| III. Preexisting cardiac disorder |
| A. Mitral stenosis |
| B. Chronic left ventricular failure |
| C. Idiopathic hypertrophic subaortic stenosis |
| IV. Preexisting extracardiopulmonary disorder |
| A. Primary and secondary hyperparathyroidism |
| B. Hypervitaminosis D |
| C. Pyloric stenosis with alkalosis |
The mechanism(s) of lung calcification with or without ossification is not precisely known. No single factor is responsible. Figure 1A
Figure 1. Elements that may lead to metastatic calcification with or without ossification. The diagram shows that factors that lead to (A) metastatic calcification may also lead to (B) pulmonary ossification but that additional factors are likely required (discussed in text). BMP = bone morphogenic protein; IL = interleukin; TGF-β = transforming growth factor-β; VEGF = vascular endothelial growth factor.
[More] [Minimize]Two physiologic requirements for metastatic calcium deposition are the release of excess calcium salts from bone and their transport through the circulation (10). The inorganic component of bone is comprised of apatite minerals with the chemical formula Ca3(PO4)2 · CaX2 where X2 may represent carbonate (CO3), difluoride (F2), dihydroxide ([OH]2), oxygen atom (O), or sulfate (SO4). For conditions that promote calcium release from bone, such as an elevated hydrogen ion concentration, the liberated Ca3(PO4)2 and CaCO3 salts are transported via the blood in soluble form. This is primarily as calcium hypophosphate (CaHPO4), which then reprecipitates as Ca3(PO4)2 and CaCO3 salts in tissues that have a favorable physicochemical environment such as an alkaline pH and a propitious chemical stoichiometry (10).
Although metastatic calcification occurs with normal or even low serum calcium levels, an elevated calcium–phosphate product of more than 70 mg2/dL2 (normal product is approximately 40 mg2/dL2) favors this process (18, 32). Pulmonary metastatic calcification has been identified in patients who succumbed to severe systemic calcinosis from fulminant hyperparathyroid crisis (33–35). There are, however, a few studies that have not supported a correlation between metastatic calcification and the level of the calcium–phosphate ion product (5, 36–38). In cases of metastatic calcification with a normal calcium–phosphate product, it has been hypothesized that previous or current azotemia, an elevated parathyroid hormone, and/or exogenous vitamin D “sensitize” the tissues (Figure 1A). This proposes that previous priming with a calcifying factor, followed by exposure to a challenging agent (e.g., calcium salts, tissue injury, or physical stress), is the basis for pulmonary calcification (39). This hypothesis is supported by a dog model of chronic renal failure (CRF) in which the parathyroid hormone and calcium content of the lungs were increased in the CRF dogs with intact parathyroid glands but not in parathyroidectomized animals (40). Moreover, those with intact parathyroid glands had pulmonary hypertension, supporting the functional relevance of metastatic lung calcification.
Pulmonary parenchymal granulomas and mediastinal and hilar lymphadenopathy associated with fungal diseases, tuberculosis, and sarcoidosis may calcify even in the face of normal serum calcium levels. Although this dystrophic calcification occurs in injured and abnormal tissues, macrophages within granulomas may also produce 1,25 vitamin D, thereby increasing intestinal absorption of calcium and phosphate and providing an additive or synergistic factor that promotes calcification in these tissues (41, 42). This may occur in the absence of detectable increases in serum calcium levels, similar to the ability of supplemental vitamin D and calcium to increase bone density without necessarily raising serum calcium levels.
Calcium salts precipitate in an alkaline environment. In vitro, the usefulness of the calcium–phosphate product in predicting metastatic calcification is compromised in solutions that deviate in either direction from a pH of 7.3. Although impractical in the clinical setting, the calcium–HPO4−2 product is a more accurate predictor of the risk for calcification because it varies with the pH. For example, for a calcium–phosphate product of 44, the calcium–HPO4−2 product is 2.9 × 10−6 in a pH of 3.5 and 2.1 × 10−6 in a pH of 6.8 (43). Thus, in a more alkaline environment, the critical calcium–phosphate product that results in calcium salt precipitation is lower, and conversely, in a more acidic milieu, the calcium–phosphate product that results in calcification is higher (43). This hypothesis gains support from the observation that organs susceptible to metastatic calcification, such as the stomach, kidneys, and lungs, secrete free hydrogen ions, creating an alkaline tissue environment (10, 44). Because the serum is normally saturated with respect to CaHPO4 and an alkaline pH favors retention of this compound, the following reactions could account for the increased delivery and precipitation of Ca3(PO4)2 and CaCO3 in soft tissues with alkalinity (10):
 |
 |
In this regard, it is interesting to speculate that the pH of the blood in the lung is more alkalotic compared with other organs because of CO2 removal. Furthermore, it has been suggested that the upper lobe predilection of some pulmonary calcific disorders is explained by a higher blood pH (approximately 7.51) and lower PaCO2 (approximately 30 mm Hg) at the apex compared with the relatively lower pH at the base (Figure 2)
Figure 2. Differences in the pH and ventilation–perfusion (·V/Q·) ratio between the apex and base of the lungs. The increased ventilation–perfusion ratio in the lung apex resulting in decreased PaCO2 and increased pH is a hypothesized mechanism by which metastatic calcification has a greater propensity to occur in the upper lobes.
[More] [Minimize]Cessation of pulmonary blood flow can lead to pulmonary calcification (37, 52). This has also been partially attributed to tissue alkalosis. Bloodworth and Tomashefski described seven patients with localized pulmonary calcification distal to pulmonary artery obstruction from thrombus or intra-arterial tumor (37). This calcification did not require co-existing infarction, pneumonia, or diffuse alveolar damage. They suggested that obstruction of blood flow to a segment of lung resulted in decreased CO2 delivery, and this, in association with hyperventilation resulting from the vascular occlusion, lowered the alveolar Pco2, causing tissue alkalosis and setting the stage for calcium salt deposition.
Because several isoforms of alkaline phosphatase, an enzyme that elevates the calcium–phosphate product by catalyzing the production of free phosphate, exhibit optimum activity at an alkaline pH (53), alkalosis may in addition predispose to ectopic calcification by this mechanism (Figure 1A). Alkaline phosphatase also enhances osteoblastic activity and thus may be necessary for pulmonary ossification to occur (Figure 1B). Although the presence of elevated alkaline phosphatase and phosphate levels has not been systematically evaluated in pulmonary calcification or ossification, these compounds are increased in the heterotopic ossification of joints secondary to spinal cord injury (54). Present in practically all tissues, alkaline phosphatase is abundantly expressed by alveolar type II cells and nonciliated bronchiolar (Clara) cells (55). Gomori showed that phosphatase activity colocalized with pathological calcification, suggesting that alkaline phosphatases may indeed play an active role in soft tissue calcification and ossification (56). However, this does not explain why calcification fails to occur in healthy tissues normally rich in alkaline phosphatase, such as the kidney and intestinal mucosa (57). Perhaps other factors, such as a local increase in free calcium ions in injured tissues, lower the threshold for calcification.
In contrast to metastatic calcification, dystrophic pulmonary calcification occurs in sites of previous cellular and tissue injury. Calcium is an important ion for cellular integrity, and an increase in intracellular calcium may contribute to the injury. For example, cell necrosis occurring from oxidant injury and inflammation is due, in part, to an increase in free cytosolic calcium. This increase results from a net influx of extracellular calcium across the plasma membrane and the release of intracellular calcium from mitochondria and the endoplasmic reticulum (58) (Figure 3)
Figure 3. Hypothesis by which cellular injury predisposes to dystrophic calcification (discussed in text) (modified from Cotran [58]).
[More] [Minimize]Accelerated respiratory failure caused by extensive calcification of the alveolar septae has been seen (5, 60, 61). Two patients with hypercalcemia, one caused by B-cell lymphoma and the other caused by multiple myeloma, developed fatal acute respiratory distress syndrome (61). Autopsy revealed widespread calcification in addition to the diffuse alveolar damage. Although chronic hyalinized intra-alveolar exudate may become fibrotic and calcify (61), the calcification in these patients was disseminated and their demise rapid, making it less likely that the acute respiratory distress syndrome per se predisposed to the calcification. Instead, it is more likely that the metastatic calcification predisposed to the lung injury by disrupting the normal alveolar–capillary wall or, alternatively, the two processes were independent events.
In the context of bone formation, angiogenesis and osteogenesis are mutually dependent (62). Angiogenesis is a critical process in normal osteogenesis and also may be central to ossification in the lungs. For ossification of injured soft tissues, there is a sequential transformation of fibroblasts first to chondroblasts and then to osteoblasts. This transformation occurs in the presence of both venous stasis and arteriovenous shunting (63). The role of angiogenesis in pulmonary calcification is less clear. Some potential pathophysiologic links between angiogenesis and osteogenesis include the following: (1) osteogenic protein-1, a bone growth factor that upregulates alkaline phosphatase activity and osteoblastic cell differentiation, also enhances the synthesis of vascular endothelial growth factor, a potent angiogenic growth factor for osteoblasts (62). Conversely, disruption of vascular endothelial growth factor synthesis or function inhibits osteogenic protein-1–induced alkaline phosphatase activity and bone formation. (2) Parathyroid hormone, elevated in certain pulmonary calcific disorders, also stimulates vascular endothelial growth factor mRNA expression (64). (3) Prostaglandin E1 and prostaglandin E2, potent stimulators of bone formation in vivo, promote vascular endothelial growth factor production (65); and (4) other angiogenic factors important for bone formation under hormonal control including endothelial cell stimulation angiogenic factor and other novel molecules seem to play a role (66–68). Despite the strong association between angiogenesis and physiologic ossification, the role of angiogenic factors in pulmonary ossification and metastatic or dystrophic pulmonary calcification is yet to be determined.
The extent of physiologic impairment associated with calcium deposition does not necessarily correlate with the degree of macroscopic calcification; that is, some patients with extensive calcification may be asymptomatic, whereas others with more subtle calcification in the face of normal chest radiographs may have significant physiologic impairment. High-resolution computer tomography (HRCT) scan and 99mtechnetium-methylene diphosphate (99mTc-MDP) bone scintigraphy are more sensitive and specific than the chest X-ray for the detection of pulmonary calcification. Their main use is the early recognition of lung calcification or ossification in at-risk individuals, thereby precluding the necessity for surgical lung biopsy to identify unexplained chronic pulmonary infiltrates.
The chest radiograph is useful for the detection of pleural calcification, hilar-mediastinal lymph node calcification, calcified lung nodules, and with less sensitivity, diffuse parenchymal calcification. Even when seen on chest radiograph, diffuse calcification is often mistaken for another process such as pulmonary edema or intrapulmonary hemorrhage, as it appears as nondiscrete infiltrates (33). Similarly, localized pulmonary calcification is often confused with infarction, pneumonia, or malignancy (8, 32, 48, 69–71). In patients in whom there is an increased risk for metastatic calcification, additional studies are usually required, particularly in those with radiographically stable pulmonary opacities.
Three nonmutually exclusive patterns of pulmonary parenchymal calcification may be seen by HRCT scan (Figure 4)
Figure 4. Illustration of HRCT findings of histologically proven metastatic or dystrophic calcification. The varied radiographic manifestations are discussed in the text and are not mutually exclusive. Although the histopathologic features of each have not been precisely correlated, the array of findings is likely caused by an assortment of inflammation coupled to the pulmonary calcification. The sizes of the nodules are drawn proportionately bigger for the sake of visibility.
[More] [Minimize]
Figure 5. Chest radiograph and CT scan of a patient with metastatic calcification caused by CRF on hemodialysis. (A) The chest radiograph reveals subtle bilateral opacities in both lung fields in a patient with biopsy-confirmed metastatic calcification (arrows). (B) Lung image of a non-HRCT (10-mm thick slices) of the chest demonstrates ill-defined centrilobular calcified nodules scattered diffusely through the lungs, much more apparent than on the chest radiograph. In C, however, the mediastinal images showed no visible calcified lesions, likely due to the microscopic size of the calcified lesions, a relatively large soft-tissue component resulting in an overall low attenuation caused by signal averaging and the relatively thick slices (10 mm) of the CT scan.
[More] [Minimize]
Figure 6. Histopathology of pulmonary metastatic calcification in a patient with CRF on hemodialysis. Note that the calcified lesions (arrows) assume various shapes and are primarily located in the thickened fibroproliferative interstitium of the lungs (hematoxylin and eosin, original magnification ×100).
[More] [Minimize]In a CRF patient with bilateral upper lobe metastatic calcification, lung magnetic resonance imaging revealed nodular lesions with a higher lesion to skeletal muscle signal intensity ratio on T1-weighted imaging than on the T2-weighted imaging (75). However, magnetic resonance imaging is relatively insensitive for detecting pulmonary calcification and is not recommended. The spatial resolution of magnetic resonance imaging is low in the lungs, and in addition, neither calcium nor air in the lung typically transmits a signal, thereby failing to produce a contrast.
Because pulmonary calcification is often misinterpreted as pneumonia or pulmonary edema both on the chest radiograph and CT scan, bone scintigraphy with the bone-avid radiotracer 99mTc-MDP helps sort out equivocal cases (16, 48, 76–78). Figure 7
Figure 7. Bone scintigraphy of a patient with metastatic calcification due to CRF and on hemodialysis. Note the increased uptake of 99mTc-MDP calcium-avid radiotracer in both lungs (right greater than left) and the stomach.
[More] [Minimize]It has been proposed that in uremia, 99mTc-MDP scintigraphy has a lower sensitivity for detecting pulmonary calcification when compared with hyperparathyroidism or malignancy (84). This difference is perhaps due to the relatively lower uptake of 99mTc-MDP by amorphous whitlockite type mineral ([CaMg]3[PO4]2) compared with hydroxyapatite crystals (Ca10[PO4]6[OH]2), the former being the predominant calcium salt in renal failure-associated metastatic calcification (84). Nevertheless, in 23 patients receiving maintenance hemodialysis but without evidence of pulmonary calcification on chest radiograph, 14 (61%) were prospectively found to have a positive 99mTc-MDP bone scan of the lungs. The only distinguishing clinical feature in those with a positive scan was a longer duration of hemodialysis (38 ± 5 months) than for those with negative scans (12 ± 4 months) (85).
The standard chest roentgenogram is relatively insensitive for the detection of diffuse pulmonary calcification with or without ossification. Typically, the study is negative or the infiltrates cannot be distinguished from other parenchymal processes. Exceptions are large and densely calcified parenchymal nodules, lymph nodes, or pleura. HRCT mediastinal images and 99mTc-MDP bone scintigraphy are relatively specific for pulmonary calcification and ossification. There are, however, two important caveats concerning the CT diagnosis of ectopic calcification and ossification: (1) The presence of dense lesions on lung window images will not distinguish between noncalcified and calcified opacities and conversely, (2) because of signal averaging, the failure to detect calcification or ossification on mediastinal images does not unequivocably exclude the possibility if the calcified lesions are microscopic, if there is a relatively large soft tissue component, and/or if standard 10-mm slices are imaged. Although bone scintigraphy appears to be more sensitive than CT scans in detecting ectopic calcification and ossification, this observation is based on anecdotal case reports without prospective comparison studies. One advantage of the CT scan is that the thorax and lung parenchyma can also be evaluated in detail. The advantage of scintigraphy is that other organs can be concurrently evaluated for metastatic calcification or ossification.
In this section, we discuss in greater depth specific disorders of pulmonary calcification and ossification that illustrate the mechanistic principles and imaging features described in the previous sections.
In this subsection, we highlight those conditions associated with metastatic calcification for which some pathophysiologic explanation exists, although much remains unknown. Metastatic pulmonary calcification is associated with a variety of benign and malignant disorders (Table 1). The prevalence in an unselected population is relatively low. In a retrospective review of over 7,000 autopsies, only 14 cases of metastatic calcification were identified: three with CRF, seven associated with tumor-induced bone destruction, and four with hyperparathyroidism (86). In contrast, metastatic pulmonary calcification was found in 60–75% of hemodialyzed patients at autopsy (5, 38). Conger and colleagues prospectively studied pulmonary calcification in chronically hemodialyzed patients who subsequently died (5). In the nine with lung parenchymal calcification, only one had premorbid chest radiographic evidence of pulmonary infiltrates. The calcium deposits were located in the alveolar epithelial basement membranes, the alveolar capillary walls, the bronchial walls, and the media of pulmonary arterioles. Figure 6 demonstrates the histopathologic features of diffuse metastatic pulmonary calcification in a CRF–hemodialysis patient. As seen in the figure, there is an associated interstitial fibroproliferative response, leading to further restrictive physiology (38, 87, 88). Calcium phosphate represents the principal mineral salt of CRF-associated metastatic calcification, which is similar to the composition of normal bone or dystrophic calcification (89). X-ray diffraction analysis indicates that the predominant crystal configuration is whitlockite with a smaller amount of calcium pyrophosphate (CaP2O7). The whitlockite pattern of CRF-associated metastatic pulmonary calcification is distinct from the hydroxyapatite variety, typically found in other forms of pulmonary and soft-tissue metastatic calcifications (84, 90).
In CRF patients undergoing hemodialysis, four conditions predispose to metastatic calcification. First, acidosis leaches calcium and phosphate from bone. Second, there is increased parathyroid hormone secretion caused by a negative calcium balance created by the failure of the kidneys to convert 25 vitamin D to 1,25 vitamin D, resulting in increased calcium and phosphate release from bone. Although patients with this secondary form of hyperparathyroidism are already at risk for metastatic calcification (91, 92), occasionally the stimulated parathyroid gland becomes autonomous, resulting in tertiary hyperparathyroidism and severe hypercalcemia (93). Third, intermittent alkalosis, which often accompanies bicarbonate hemodialysis, predisposes to soft tissue precipitation of calcium salts. This is supported by the observation that metastatic soft tissue calcification is accelerated following hemodialysis (5, 38, 94). Finally, the decreased glomerular filtration of phosphate may contribute to an elevated serum calcium–phosphate product. Elevated serum phosphate levels have been shown to correlate highly with vascular calcification in uremic patients (95). This observation was experimentally confirmed in cultured human aortic smooth muscle cells in which media containing phosphate levels comparable to those seen in hyperphosphatemic patients showed dose-dependent increases in cell culture calcium deposition (95). In contrast to the relatively physiologically benign course of pulmonary calcification in most patients, severe cases have been described (5, 70, 88, 96, 97). For example, in a patient with long-standing renal insufficiency and nephrotic syndrome, widespread metastatic calcification of multiple organs occurred after 3 months of bicarbonate hemodialysis (94). Although the calcium–phosphate product was normal, the free calcium index was elevated because of depressed serum protein, leading to ectopic calcium–phosphate deposition.
In 91 patients who underwent orthotopic liver transplantation, chest radiographs, despite their relative insensitivity, detected pulmonary calcification in 5.2% (8). The mechanism is unclear. Complicating renal failure, acid-base abnormalities, and the administration of exogenous calcium and citrate have been proposed as contributing events. Elevated plasma citrate concentrations caused by the administration of packed red blood cells could lead to metabolic alkalosis and calcium chelation, prompting parathyroid release of parathyroid hormone. This gains support from the observation that the patients with calcification had higher levels of phosphorus and calcium postoperatively and had received more intraoperative blood products, all containing exogenous calcium (8).
Although metastatic calcification most often accompanies a benign systemic metabolic disorder, it may also be associated with a variety of malignancies in which a common pathophysiologic attribute is the presence of hypercalcemia and/or an elevated calcium–phosphate product (Table 1) (98). Here the hypercalcemia may either be hormonally mediated or may result from metastasis to bone. Metastatic calcification is rare, however, even for these malignancies. In the case of osteogenic sarcoma, the ectopic calcification is secondary to the metastatic tumor itself.
The clinical importance of metastatic calcification in slowly progressive cases is the confusion it creates in the evaluation of an abnormal chest radiograph in patients at risk for this process, particularly those undergoing hemodialysis or individuals with elevated calcium–phosphate product. In extensive pulmonary calcification, a restrictive physiology, a decreased diffusion capacity, and hypoxemia result (33). Rarely, progressive respiratory insufficiency and death may ensue (9, 99). 99mTc-MDP scintigraphy or mediastinal images on HRCT scan may be diagnostic of metastatic calcification without need for further investigation. The Von Kossa stain is significantly more sensitive than the standard hematoxylin and eosin stain in detecting calcium in tissues (100). Electron microscopy is even more sensitive and can show specific intracellular and extracellular sites of calcification, although it is not generally clinically available (101). Specific treatment is aimed at correction of isolated hyperphosphatemia or elevated calcium–phosphate product, if present. Successful renal transplantation may ameliorate metastatic pulmonary calcification (91), and conversely, renal graft failure and persistent uremia may accelerate, by some unexplained mechanism, the ectopic calcification (102). Moreover, metastatic pulmonary calcification may inexplicably progress despite a normally functioning renal allograft and normal or near-normal calcium and phosphate levels, although occult tertiary hyperparathyroidism may be responsible for some of these rare cases (96, 97). In severe recalcitrant cases associated with primary or tertiary hyperparathyroidism, parathyroidectomy is indicated (96).
Microbial infections that elicit a granulomatous tissue response can also result in a variety of thoracic dystrophic calcifications (Table 1). H. capsulatum–related thoracic calcifications include calcified mediastinal lymph nodes/broncholithiasis, mediastinal granuloma, and solitary or multiple calcified histoplasmomas (103, 104). In addition to single or several large histoplasmomas, there may be numerous, small, diffuse, calcified pulmonary nodules in asymptomatic patients (Figure 8A)
Figure 8. Chest radiograph and CT scan of a patient with diffuse nodular calcification associated with healed histoplasmosis. (A) The chest radiograph revealed small, well-circumscribed calcified lesions distributed diffusely but more prominent in the right mid-lung field. (B) A lung window image of the CT scan confirms the fine dense nodules, but the mediastinal image (C) revealed a paucity of calcified lesions. This discrepancy is likely because 10-mm slices were obtained, resulting in a signal averaging effect.
[More] [Minimize]Pulmonary calcification as a sequela of C. immitis infection is uncommon (109). However, regressive changes of coccidioidal pulmonary lesions may result in single or multiple dystrophic calcified nodules.
Tuberculosis produces a number of chest calcifications. Dystrophic calcification may manifest in parenchymal granulomas, mediastinal lymph nodes, and fibronodular areas of lung involvement. Diffuse nodular calcification of the lungs may follow treatment of a hematogenous infection (24). Roussos and coworkers recently showed that patients with tuberculosis can develop hypercalcemia caused by excessive production of endogenous 1,25 vitamin D, thus further predisposing to dystrophic pulmonary calcification (110). In a rabbit model of tuberculosis, early granulomatous inflammation without necrosis lacked phosphatase activity (56). However, when caseous necrosis occurred, there was robust phosphatase activity within the necrotic centers. Subsequent calcification was invariably found in the phosphatase-positive areas. Clinically, tuberculous calcification enhances tissue friability at surgery but is generally inconsequential and does not affect mortality.
In unusual instances, sarcoidosis may produce multiple micronodular calcifications, radiographically similar to PAM (111). In contrast, however, their histologic features are distinct: In sarcoidosis, calcification is confined to the epitheloid granulomas, and in PAM, there are distinct intra-alveolar microliths.
Although less than 5% of chickenpox cases occur in adults, adult infections are associated with a higher incidence of pneumonic complications. Radiographically, varicella pneumonia typically shows scattered ill-defined nodular or reticular densities. The infiltrates usually resolve over time, but in some cases, asymptomatic miliary calcifications appear 3 to 5 years following the acute event (Figure 9)
Figure 9. Chest radiograph demonstrating the punctate pulmonary calcification as a sequela of adult varicella pneumonia (reprinted with permission from Schwarz and King [164]).
[More] [Minimize]Late development of pulmonary calcification from previous smallpox virus exposure has also been illustrated (26, 114). In nurses who developed flu-like illnesses within days of exposure to a smallpox patient, radiographic studies often showed poorly defined nodular opacities, attributed to a modified variola pneumonia. After clinical resolution of the acute illness, follow-up chest radiographs revealed extensive well-defined punctate calcifications without physiologic abnormalities (26). Other DNA viruses such as herpes simplex have been reported to lead to calcification (115). In an infant who died from presumptive herpes simplex pneumonia, the alveolar septae were extensively calcified (112). This case was unusual because fulminant calcification complicated the acute phase of the disease.
Pulmonary and thoracic lymph node calcifications associated with P. carinii infection, with or without concomitant human immunodeficiency virus infection, have been described, albeit uncommonly (116–119). Widespread visceral calcification has also been reported in disseminated pneumocystosis (120, 121). In some cases, the pulmonary and extrapulmonary calcification was associated with a granulomatous response to the infection (28, 116, 117, 119, 120). In a human immunodeficiency virus–positive individual receiving aerosolized pentamidine, extensive upper lobe calcification was observed (122). However, in contrast to the upper lobe distribution, which occurs in some cases of metastatic calcification, this was likely due to the suboptimal delivery of aerosolized pentamidine to the upper lobes. In a detailed pathologic study of 13 cases of pneumocystosis-associated pulmonary calcification, various calcification patterns were seen, the most common being a “bubbly” appearance in which aggregates of punctate calcification were admixed with P. carinii cysts (28). An important diagnostic pearl is that this pattern was not associated with the typical intra-alveolar foamy exudate seen with active pneumocystosis. Both parenchymal and pleural calcification can also occur with P. westermani pulmonary infection and are thought to be related to the calcified mummification of the parasite (27).
Primary amyloidosis results from the abnormal production and tissue deposition of light chain (AL) protein, derived from the variable portion of the immunoglobulin light chain. Because amyloid fibrils have an affinity for calcium, secondary calcification can occur in amyloidosis (123). The lungs are affected in up to half of patients with primary amyloidosis, appearing as either localized or diffuse disease of the airways or lung parenchyma (124, 125). The calcified lung lesions associated with diffuse parenchymal amyloidosis are typically characterized radiographically by interstitial or mixed interstitial-alveolar infiltrates, admixed with varying degrees of calcification—rarely ossification—and located predominantly in the subpleural regions of the mid and lower lung zones (126) (Figures 10A and 10B)
Figure 10. Chest radiograph (A) and mediastinal window CT scan (B) of dystrophic pulmonary calcification in primary amyloidosis (arrows).
[More] [Minimize]Detectable PVCs, although uncommon, usually indicate a significant underlying chronic condition. Because PVCs occur in areas of high flow, they are detected in larger vessels (31). However, little is known about their pathogenesis. Similar to the evolving knowledge of the pathogenesis of calcification in the pulmonary parenchyma, there are parallel advances in understanding regulation of vascular calcification.
Atherosclerosis is unusual in the pulmonary circulation, where the mean arterial pressures are significantly lower than in the systemic circulation (127). For atherosclerosis to occur in the pulmonary circulation, it appears to require both an increase of the mean arterial pressure and a pathologic state, which produces high flow. Atherosclerosis may be seen in long-standing pulmonary hypertension in patients with primary pulmonary hypertension (128–130) and those with congenital heart disease (127).
Although there is little direct investigation on the cell biology of PVC, parallels between PVC and systemic arterial calcification can be made. In atherosclerotic systemic vessels, calcium deposits and lamellar bone form at the intimal medial interface or within the media of the blood vessel (131). Using in situ hybridization, bone morphogenic protein-2, an osteogenic differentiation factor, is expressed in the calcified vascular lesions (Figure 1B) (131). Pericytes, cells that surround pulmonary vessels and are instrumental in regulating angiogenesis, can differentiate into osteogenic cell lines (132). Thus, they have the potential to orchestrate calcification or bone formation in the pulmonary vasculature. Vascular endothelial growth factor, a potent mitogen involved in the hypoxic vascular response, is one potential link between hypertensive remodeling with calcification or ossification (see The Role of Angiogenesis in Proposed Mechanisms of Ectopic Lung Calcification and Ossification and Figure 1) (133). Further investigation of PVC could provide insights into the role of physical stresses such as high wall shear stress in the modulation of growth factors that redirect differentiated cells into an osteogenic program.
Conditions producing increased vascular wall shear stress or high flow are presumed to be important for the formation of dystrophic PVC for the following reasons: (1) There is an increased susceptibility of vascular grafts to calcification (134). (2) There are PVCs in clinical states associated with increases in either vessel wall shear stress or increased pulmonary blood flow and pulmonary hypertension, and (3) in utero development of PVC with severe volume overload has been seen (135).
High wall shear stress, the presumed pathogenetic condition that most often leads to calcification, accompanies vascular grafting in the pulmonary circulation. In children with cyanotic congenital heart disease who underwent a modified Blalock-Taussig shunt procedure with placement of vascular grafts, graft removal years later demonstrated areas of active angiogenesis and adjacent graft calcification (134). Sites of pulmonary artery contact with saphenous vein grafts used for coronary artery bypass demonstrate pulmonary artery calcification visible on CT scan (136). Although the mechanisms of graft calcification are unknown, the application of heparin on prosthetic vascular grafts, including pulmonary artery grafts, diminishes calcification, suggesting a role for coagulation (137).
High shear forces and calcification also occur in pulmonary hypertension most often as the result of congenital heart disease. Early reports of pulmonary artery calcification described radiographic calcification in the main pulmonary arteries or large branch vessels in severe long-standing pulmonary hypertension with elevated pulmonary vascular resistance and a right to left shunt (Eisenmenger's syndrome) (138). Pulmonary artery calcification has also been reported in a left to right shunt from patent ductus arteriosis and long-standing ventricular and atrial septal defects (138–141).
In in utero twins with a common heart and high-flow and volume overload, pulmonary artery calcifications were present in the large vessels adjacent to the functioning heart (135). Histologically, there was hyperplasia of the intimal and medial layers and disruption and calcification of the medial elastic fibers. This appearance is similar to that described in the autosomal recessive disorder of idiopathic arterial calcification of infancy (142). Calcification may also occur with pulmonary venous hypertension and hemosiderosis, particularly in the setting of long-standing mitral stenosis (130). Idiopathic pulmonary hemosiderosis has also been associated with calcification of the elastic lamina of pulmonary arteries, arterioles, and veins (130), possibly through a combination of hemorrhage-induced inflammation with or without increased shear stress.
PVC occurs as a result of high shear stress of long duration. The role of injury and inflammation and accompanying angiogenesis and vascular smooth muscle cell reprogramming to an “embryonic osteogenic program” is of possible importance. Recent work suggests that calcification of the medial layer in systemic vessels from end-stage renal disease patients is associated with increased bone morphogenic protein and alkaline phosphatase activity, potentially linking the metastatic calcification process to vascular calcification as well (143). The major clinical importance of finding PVC is the implication of the chronicity and severity of the underlying condition.
PAM, a rare disorder of unknown etiology, is recognized by the intra-alveolar accumulation of spherical calcified concretions (144). Most patients are between 30 and 50 years of age when first discovered. Although there is a familial association in at least 50% of the cases, common environmental factors could also account for this observation (145, 146). This disease is especially prevalent in Turkey, representing 33% of the world literature (147), although reporting bias cannot be totally excluded. There is no evidence that infection plays a role. An isolated inborn error of calcium metabolism in the lungs has been proposed, but circulating calcium and phosphorus levels are consistently normal in PAM. It is speculated that, due to an unknown stimulus, changes in the alveolar lining membrane or secretions result in greater alkalinity, promoting intra-alveolar precipitation of calcium phosphates and carbonates (148). Coetzee described a patient with PAM, with similar pathologic and radiographic findings in the lumbar sympathetic chains and testes, suggesting that PAM was a systemic disorder in this individual (145).
Asymptomatic cases, even with extensive radiographic involvement, are often discovered incidentally. Cough and dyspnea are the most common presenting symptoms and usually occur late in the course of the disease. Normal or mild restrictive pulmonary physiology may be present in the asymptomatic individual. With progressive disease, severe lung restriction may ensue with impairment of the diffusing capacity and gas exchange abnormalities. The chest radiograph shows bilateral, sand-like, micronodular calcified densities known as microliths or calcispherites, which are usually less than 1 mm in diameter (149). They appear concentrated in the lower two-thirds of the lung, often obliterating the diaphragmatic, mediastinal, and cardiac borders (Figure 11)
Figure 11. Chest radiograph of a patient with PAM. Note the predominantly perihilar infiltration of fine dense nodules that obliterate the cardiac and medial diaphragmatic borders (reprinted with permission from Schwarz and King [164]).
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Figure 12. Lung histopathology from a patient with alveolar microlithiasis revealing calcified microliths (arrows) localized to the intra-alveolar spaces. Some of the interstitial spaces are thickened by inflammation and collagen deposition (arrowheads) (hematoxylin and eosin, original magnification ×100).
[More] [Minimize]Bone formation with or without marrow components occurring in the interstitial and alveolar compartments is unusual. Pulmonary ossification can be idiopathic or be associated with a variety of underlying pulmonary, cardiac, and systemic disorders (154–160). As can be seen in Table 2, many of the conditions associated with pulmonary ossification also occur with metastatic or dystrophic calcification; thus, ossification could represent a continuation of either process in the lung (161, 162).
The pathogenesis of pulmonary ossification is unknown. Serum calcium and phosphorus levels are usually normal. Unlike heterotopic ossification that occurs around joints in association with spinal cord injuries (54), the serum alkaline phosphatase levels in pulmonary ossification are generally within normal limits, although this has not been consistently evaluated. In cases associated with pulmonary venous congestion, chronic intra-alveolar hemorrhage has been implicated as a predisposing factor for subsequent fibrosis and ossification (163). Ossification is the sequela of a series of events beginning with degeneration of the arterial media, followed by inflammation and hyalinization of the perivascular tissue. Growth factors from cells involved in this extracellular matrix formation and resolution of inflammation may also play a role in ossification (Figure 1). Transforming growth factor-β is elaborated by inflammatory macrophages and damaged epithelial cells and represents a critical growth factor for collagen and the extracellular matrix. Transforming growth factor-β, strongly implicated in idiopathic pulmonary fibrosis and other fibrotic pulmonary diseases (164), also stimulates osteoblast and chondrocyte proliferation. Another growth factor that may play an important role in ectopic pulmonary ossification is bone morphogenic protein, a member of the transforming growth factor-β superfamily (165). Bone morphogenic protein, which is likely important in the development of familial primary pulmonary hypertension (166), induces ectopic bone formation in the rat submandibular gland (167). Interleukin-1 has also been shown to enhance bone morphogenic protein–induced hereotopic ossification in laboratory animals (168). The profibrotic cytokine interleukin-4, in conjunction with monocyte-colony stimulating factor, may also transform human alveolar macrophages to osteoclasts, a cell important in bone remodeling (59). Although the role of fibrogenic, angiogenic, and osteogenic growth factors and cytokines in idiopathic and secondary pulmonary ossification is unexplored, their influence may potentially induce ossification in fibroproliferative pulmonary disorders such as idiopathic pulmonary fibrosis.
Pulmonary ossification has features of both experimentally induced bone formation and embryologic bone development (169). Local ionic charges, inflammation, and tissue anoxia promote the transformation of cultured fibroblasts into osteoblasts (170, 171). Stress forces that normally shape growing bone also stimulate cell proliferation. In an analogous fashion, shear stresses in noncompliant lung tissue due to fibrosis may induce the conversion of fibroblast to osteoblasts and ultimately bone formation (170).
The interstitial deposition of bone can be localized or widely distributed throughout the pulmonary parenchyma. Two histologic types of pulmonary ossification have been described (159): (1) a nodular circumscribed form and (2) a dendriform type. The nodular form is characterized by lamellar deposits of calcified osteoid material situated within the alveolar spaces often without marrow elements (Figure 13A)
Figure 13. Lung histopathology of pulmonary ossification. (A–C) The findings in a patient with IPO. (A) The ossified lesion is of the nodular type, and (B and C) it is of the dendriform type with bone spicules and bone marrow elements. Both types were found in the same patient. (D) Ossified pulmonary lesions are from a patient with biopsy-proven usual interstitial pneumonitis (idiopathic pulmonary fibrosis) (hematoxylin and eosin, original magnification ×40).
[More] [Minimize]IPO most often is found in men over age 60 but also has been reported in younger adults and in women. Patients can be asymptomatic or have minimal complaints, and IPO represents an unexplained radiographic finding. Many cases are diagnosed at autopsy. A restrictive pulmonary physiology with low diffusion capacity is present when disease is extensive (156, 175). In the secondary forms, signs, symptoms, and the physiologic abnormalities are more likely due to the accompanying disorder. It is uncommon for pulmonary ossification to be seen on the chest radiograph. When present, it involves the lower lobes, appearing as nonspecific reticulonodular densities (74) (Figure 14A)
Figure 14. The chest radiograph and HRCT scan of a patient with IPO. (A) Coarse reticular opacities are noted in the lower lung zones. In the lung window images of the HRCT (B), there are thickened reticulonodular infiltrates mainly at the peripheral bases. In the mediastinal images of the HRCT with 1-mm thin slices (C), the bone density of the lesions is confirmed.
[More] [Minimize]Pulmonary calcification and ossification are relatively rare and often asymptomatic. Several predisposing conditions are associated with pulmonary parenchymal calcification with or without ossification. These include hypercalcemia, hyperphosphatemia, alkalosis, and lung injury in the presence or absence of conditions that result in angiogenesis and increased pulmonary blood flow causing elevated vessel wall shear stress. The clinical states associated with pulmonary calcification include several major diseases including CRF, orthotopic liver transplantation, granulomatous infection, infection by DNA viruses or parasites, pulmonary amyloidosis, and pulmonary vascular disease; PAM is considered a unique form of ectopic pulmonary calcification. For some conditions, for example, pulmonary fibrosis or PVC, the calcification may be a marker of disease severity and accelerated morbidity. Pulmonary ossification may be idiopathic or may be secondary to fibrotic lung disorders, cardiac diseases that result in pulmonary venous hypertension, or disorders that raise the calcium–phosphate product levels. The pathogenesis of pulmonary ossification may parallel that of PVC with elevations of left atrial pressure and possible high shear stress forces leading to degeneration of the arterial media, although understanding of the pathogenesis is incomplete. Current diagnostic studies may be useful in revealing pulmonary parenchymal calcification. Bone scintigraphy and HRCT scan with mediastinal images are both superior to standard chest radiography in detecting calcification and ossification when these conditions are clinically suspected.
The authors thank Dr. Robert Quaife for the 99mTc-MDP bone scan of the patient with metastatic calcification and are very grateful to Barry Silverstein for expert illustrative assistance.
Supported by grant RO1-HL66112-01A1, a Parke-Davis Atorvastatin Research Award, and the American Lung Association Career Investigator Award (E. C.); a Veterans Affairs Merit Review Award (C. W.); and a National Heart, Lung and Blood Institute–Specialized Center of Research Pulmonary Fibrosis grant HL-67671-01 (M. S.).
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